Non-insulin dependent diabetes mellitus (NIDDM) is a syndrome characterized by defects in insulin secretion and/or insulin action. Both genetic and nongenetic factors contribute to this genetically heterogeneous disorder. The past two years have seen great progress in our understanding of the molecular genetics of maturity-onset diabetes of the young (MODY), an autosomal dominant form of NIDDM with onset usually before age 25. However, there has been little progress in identifying the genes responsible for the more common late-onset NIDDM which affects more than 95% of all NIDDM patients. Studies of "candidate genes" have contributed relatively little to our understanding of the genes involved in late-onset NIDDM and we do not know how many genes may be involved, their identities, mode(s) of inheritance, or how they may interact among themselves and with environmental factors to cause late-onset NIDDM. Because of this uncertainty, we will systematically screen the human genome for late-onset NIDDM-susceptibility genes using DNA markers separated by 10 cM. Since the volume of work involved in such an endeavor is beyond the scope of a single research grant, I have joined with three other principal investigators (Drs. Graeme Bell, Pat Concannon, Craig Hanis) to submit separate but related proposals for funding. Each PI will use the same set of DNA samples obtained from patients with late-onset NIDDM and screen a designated region of the genome for "genes responsible for NIDDM". The four PIs will share all resources (DNA samples, oligonucleotide primers, etc.) and genotype data. Data management and linkage analyses will be performed on all results at two of the centers (Chicago and Houston). This will allow uniform analyses to be performed on all the markers typed. The advantage of the proposed collaborative approach is that it will be efficient and rapid. It is important to stress that the entire genome will be screened for NIDDM-susceptibility genes. The linkage studies will not be discontinued to concentrate on cloning susceptibility loci once they have been identified. It is anticipated that the identification of the NIDDM-susceptibility genes will lead to a better understanding of the molecular basis of this disorder. The results of the study will also permit the identification of at-risk subjects before the onset of clinical disease and lead to new treatment strategies based upon an understanding of the underlying molecular defects.